title: Dynamic changes in DNA methylation and hydroxymethylation when hES cells undergo differentiation toward a neuronal lineage.
abstract: DNA methylation and hydroxymethylation have been implicated in normal development and differentiation, but our knowledge is limited about the genome-wide distribution of 5-methylcytosine (5 mC) and 5-hydroxymethylcytosine (5 hmC) during cellular differentiation. Using an in vitro model system of gradual differentiation of human embryonic stem (hES) cells into ventral midbrain-type neural precursor cells and terminally into dopamine neurons, we observed dramatic genome-wide changes in 5 mC and 5 hmC patterns during lineage commitment. The 5 hmC pattern was dynamic in promoters, exons and enhancers. DNA hydroxymethylation within the gene body was associated with gene activation. The neurogenesis-related genes NOTCH1, RGMA and AKT1 acquired 5 hmC in the gene body and were up-regulated during differentiation. DNA methylation in the promoter was associated with gene repression. The pluripotency-related genes POU5F1, ZFP42 and HMGA1 acquired 5 mC in their promoters and were down-regulated during differentiation. Promoter methylation also acted as a locking mechanism to maintain gene silencing. The mesoderm development-related genes NKX2-8, TNFSF11 and NFATC1 acquired promoter methylation during neural differentiation even though they were already silenced in hES cells. Our findings will help elucidate the molecular mechanisms underlying lineage-specific differentiation of pluripotent stem cells during human embryonic development.
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 305-806, Korea.
authors.forename: Mirang
authors.initials: M
authors.lastname: Kim
authors.forename: Young-Kyu
authors.initials: YK
authors.lastname: Park
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Kang
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Lee
authors.forename: Yong-Hee
authors.initials: YH
authors.lastname: Rhee
authors.forename: Jong-Lyul
authors.initials: JL
authors.lastname: Park
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Daeyoup
authors.initials: D
authors.lastname: Lee
authors.forename: Doheon
authors.initials: D
authors.lastname: Lee
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Kim
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism / Q000031:analogs & derivatives; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000502:physiology*; D058851:GPI-Linked Proteins / Q000235:genetics; D005786:Gene Expression Regulation; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008648:Mesoderm / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D053245:RANK Ligand / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
chemical_list: D058851:GPI-Linked Proteins; D018398:Homeodomain Proteins; C108070:NKX2-8 protein, human; C497761:NOTCH1 protein, human; D009419:Nerve Tissue Proteins; D053245:RANK Ligand; C522183:RGMA protein, human; D051881:Receptor, Notch1; C505688:TNFSF11 protein, human; D014157:Transcription Factors; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt